Virus removal from liquid streams, particularly process streams in the biotech and pharmaceutical industry, has been practiced for some time. High viral clearance, high product flux, complete protein passage and simplicity of operation are the goals of the operator, yet the prior art does not provide a solution that satisfies all of these goals. Since high viral clearance is always needed, it is the other process goals that have suffered. Meeting these other goals would substantially lower processing cost.
The prior art provides several membrane types and filtration modes for viral clearance. For a general discussion concerning the state of prior art, see Chapter 20 of Filtration in the Biopharmaceutical Industry, Marcel Dekker, Inc. (1988). Chapter 20 is entitled “Filtration and the Removal of Viruses from Biopharmaceuticals.”
One of the products discussed in Filtration was the Viresolve™ product line produced by Millipore Corporation. This is a system that used a composite ultrafiltration membrane in a tight side-up-stream (TSUS) orientation in a tangential flow filtration (TFF) device.
U.S. Pat. No. 5,017,292 discloses technology used to produce the Viresolve product. It provides a composite membrane comprising a porous membrane substrate, a tight side (the surface having smaller diameter pores) having ultrafiltration separation properties and an intermediate porous zone between the substrate and the skin which intermediate zone has an average pore size smaller than that of the substrate. The intermediate zone is free of macrovoids that may break the skin. The composite membrane is capable of a log reduction value (LRV) of at least 3 (99.9% removal) of virus particles (collectively “virus”) selectively from solution. A limitation of this system is that in order to achieve adequate protein solution flux, a complex pumping system is needed to operate effectively in a TFF mode. This needed complexity results in a substantial filtration cost.
While more conventional virus removal applications are available from several manufacturers, they also cannot attain all the goals set forth above. Indeed, they either use conventional ultrafiltration membranes in single layer TSUS orientation in a TFF device or a hollow fiber ultrafiltration TFF device. They similarly lack the simplicity of use and result in a high filtration cost.
Normal flow filtration (NFF) devices, also known as dead—ended filtration devices, are currently available for use in removing viruses from process streams. Indeed, Pall Corp. of East Hills, N.Y. manufactures a dead-ended virus removal membrane under the Ultipore® DV50 brand (hereinafter the “DV50”) and DV20 brand (hereinafter the “DV20”).
The DV50 consists of three-layers of an isotropic, skinless, porous polyvinylidene fluoride (“PVDF”) membrane. While this product has the desired virus removal capabilities and simplicity of use for large virus removal, the isotropic structure of the membranes employed limits its permeability. A low permeability (water permeability of 2 Imh/psi) increases the costs of filtration. This product also does not meet all the goals set forth above.
The DV20 is a similar product, but designed for small virus removal. It has a permeability of 0.6 Imh/psi with IgG.
U.S. Pat. No. 5,736,051 discloses a PVDF membrane and method for removing viruses from solutions. More particularly, it provides an isotropic, skinless, porous PVDF membrane. We believe this is the membrane used in the DV50 and DV20.
U.S. Pat. No. 5,788,862 discloses a supported ultrafiltration membrane with a coated skin. In the patent, the membrane is described as having been used in a 2-layer configuration in NFF mode with a coated skin to filter viruses from protein streams. While satisfactory levels of virus removal were achieved, the protein passage and flux were very low: maximum disclosed flux with IgG was 0.6 Imh/psi and max IgG passage was only 84%.
In addition to the prior art providing multi-layered virus removal membranes, the prior art also provides multi-layered ultrafiltration membranes with at least one membrane being oriented TSDS. U.S. Pat. No. 4,261,834 provides two anisotropic ultrafiltration membranes positioned in series with at least one membrane juxtaposed with at least one other membrane so that substantially all the skin surface of one membrane is in intimate contact with substantially all of the skin surface of the other membrane. This invention, however, was directed to mask pinhole defects for ultrafiltration membranes used to remove proteins (pyrogens) from aqueous streams in a tangential flow filtration (TFF) system.
In light of the above, there is a clear need for filtration materials and devices that remove viruses at high log reduction values (LRV), having essentially complete passage of the protein product and operating at high flux. Furthermore, there is a need that such materials and devices should be easy to operate, preferably in NFF mode.